Synergistic composition of codine and ibuprofen to treat arthritis

ABSTRACT

The invention relates to the use of a non-steroidal anti-inflammatory drug together with an opioid analgesic in the manufacture of a medicament for the treatment of arthritis.

This is a continuation of U.S. application Ser. No. 08/584,658 filedJan. 11, 1996, now U.S. Pat. No. 5,763,452 which is a continuation ofU.S. Ser. No. 08/310,640 filed Sep. 22, 1994, abandoned.

BACKGROUND OF THE INVENTION

This invention relates to the treatment of arthritis and topharmaceutical compositions and usages therefor.

In general, the treatment of arthritic conditions has been limited tosymptomatic treatment, for example to relieve symptoms such asinflammation and pain. Thus, for example, it has been proposed to useso-called non-steroidal anti-inflammatory drug (NSAID's) in thetreatment of arthritic conditions. It has also been proposed to use avariety of analgesics, including opioid analgesics, in the relief ofpain in arthritic conditions.

It has now been found, in accordance with the present invention, thatthe treatment of arthritic conditions with both (i) an NSAID, and (ii)an opioid analgesic can serve to treat the arthritic condition itself,that is to inhibit the arthritic process.

Accordingly, one embodiment of the present invention provides the use ofan NSAID together with an opioid analgesic in the manufacture of amedicament for the treatment of arthritis (both osteoarthritis andrheumatoid arthritis). The invention also provides a method for thetreatment of arthritis by the administration to a patient of an NSAIDtogether with an opioid analgesic. The invention further providescertain pharmaceutical compositions containing an NSAID and an opioidanalgesic.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the mean clinical score per dayachieved with high dose treatment of arthritic rats using morphine,indomethacin and a combination of morphine and indomethacin versus acontrol;

FIG. 2 is a graphical representation of the mean foot pad diameter perday achieved during high dose treatment of arthritic rats usingmorphine, indomethacin and a combination of morphine and indomethacinversus controls;

FIG. 3 is a graphical representation of mean radiological score achievedduring high dose treatment of arthritic rats with morphine, indomethacinand a combination of morphine and indomethacin versus a control;

FIG. 4 is a graphical representation of the mean clinical score per dayachieved during low dose treatment of arthritic rats with morphine,indomethacin and a combination of morphine and indomethacin versus acontrol;

FIG. 5 is a graphical representation of the mean foot pad diameter perday achieved during low dose treatment of arthritic rats with morphine,indomethacin and a combination of morphine and indomethacin versuscontrols;

FIG. 6 is a graphical representation of the mean radiological scoreachieved subsequent to low dose treatment of arthritic rats withmorphine, indomethacin and a combination of morphine and indomethacinversus a control;

FIG. 7(a) is a graphical representation of the mean clinical scoreachieved during treatment of arthritic rats with indomethacin alone,morphine alone, and a combination of morphine and indomethacin versuscontrols;

FIG. 7(b) is a graphical representation of the mean foot pad diameterachieved during treatment of arthritic rats with indomethacin alone,morphine alone, and a combination of indomethacin and morphine versuscontrols;

FIG. 8(a) is a graphical representation of the mean radiological scoreachieved from treatment of arthritic rats with indomethacin alone,morphine alone, and a combination of morphine and indomethacin versuscontrols;

FIG. 8(b) is a graphical representation of the mean histological scoreachieved from the treatment of arthritic rats with indomethacin alone,with morphine alone, or a combination of indomethacin and morphineversus controls;

FIG. 9(a) is a graphical representation of the inhibition of plasmaextravasation in 5 day mBSA arthritis treated with morphine alone,indomethacin alone, and a combination of morphine and indomethacinversus a control; and

FIG. 9(b) is a graphical representation of the inhibition of plasmaextravasation in 5 day mBSA arthritis treated with codeine alone,ibuprofen alone, and a combination of codeine and ibuprofen versus acontrol.

DETAILED DESCRIPTION

The inhibition of the disease process may be manifested, e.g., by areduction in the mean radiological score of a patient who has undergoneor who is undergoing treatment in accordance with the invention. Otherparameters which could be indicative of an inhibition of the arthriticdisease process by treatment in accordance with this invention are jointdiameter, plasma extravasation and histology.

Example of NSAID's which may be used in accordance with the presentinvention include, but are not limited to, diclofenac, flurbiprofen,ibuprofen, indomethacin, ketoprofen and naproxen or pharmaceuticallyacceptable salts thereof. Examples of opioid analgesics which may beused in accordance with the invention include, but are not limited to,morphine, hydromorphone, codeine dextropropoxyphene, oxycodone,hydrocodone, and dihydrocodeine, and their pharmaceutically acceptablesalts. Examples of particular NSAID/opioid analgesic combinations whichmay be mentioned include indomethacin/morphine, ibuprofen/codeine anddiclofenac/codeine.

The daily dosage rates of opioid and analgesic and NSAID will dependupon the nature of the particular active ingredients used. By way ofexample, for a combination of morphine sulphate and indomethacin, themorphine sulphate dosage is suitably 5-300 mg, preferably 5-200 mg, morepreferably 5-60 mg (e.g. 10-60 mg or 10-40 mg) and the indomethacindosage is suitably 5-300 mg (eg. 40-200 mg), preferably 10-200 mg, morepreferably 20-80 mg; for a diclofenac/codeine phosphate combination, thediclofenac dosage is suitably 10-200 mg (eg. 25-200 mg), preferably10-150 mg (eg. 75-100 mg), and more preferably 20-80 mg, and the codeinephosphate dosage is suitably 12.5-310 mg, preferably 20-200 mg, morepreferably 40-120 mg (eg. 37.5-150 mg); and for an ibuprofen/codeinecombination, the ibuprofen dosage is suitably 300-2400 mg, preferably400-2400 mg, more preferably 400-1200 mg (e.g. 480-1200 mg), and thecodeine dosage is suitably as mentioned above.

In the case of combinations utilizing dextropropoxyphene as the opioidthe total daily dosage of dextropropoxyphene may be 32.5-260 mg,preferably 65-130 mg; in the case of dihydrocodeine (DHC) being theopioid of a combination for use in accordance with the invention thetotal daily dosage of DHC may be 20-180 mg, preferably 30-90 mg.

The foregoing dosages may represent total daily dosages for a patientundergoing treatment to inhibit the arthritic disease process. When thedosage is provided in a delayed or sustained release form, the totaldosage or appropriate sub-division of the total dosage of each activeingredient will be provided in the unit dosage form. For instance, aunit dosage form for the combination of indomethacin and morphinesulphate suitable for twice daily dosing may contain, eg., 2.5-150 mg,preferably 2.5-30 mg or 5-20 mg morphine sulphate and 2.5-150 mg,preferably 5-100 mg or 10-40 mg indomethacin. In the case of thecombination of ibuprofen and codeine, for example, a unit dosage formfor twice daily dosing may contain 150-1,200 mg, preferably 200-1,200 mgor 200-600 mg ibuprofen and 5-150 mg, preferably 10-100 mg or 20-60 mgcodeine; while for the combination of diclofenac and codeine a unitdosage form for twice daily dosing may contain 5-100 mg, preferably 5-75mg or 10-40 mg diclofenac and the above mentioned dosage of codeine.Unit dosages for twice daily dosing with combinations containingdextropropoxyphene may contain 16.25-130 mg, preferably 32.5-65 mg andthose containing DHC may contain 10-90 mg, preferably 15-45 mg of DHC.Different combinations may incorporate the amounts of active ingredientsgiven above.

Unit dosage forms containing those active ingredients which are intendedfor either once a day dosing or more frequent dosing than twice a daymay contain appropriately greater or lesser amounts of the activeingredients.

Other particularly suitable combinations may be dihydrocodeine andibuprofen; dihydrocodeine and diclofenac; dextropropoxyphene andibuprofen and dextropropoxyphene and diclofenac, at the above mentionedsuitable dosages.

It is generally desirable that the NSAID dosage be kept relatively lowsince prolonged administration of NSAID's at high dosages can, initself, lead to bone or cartilage destruction.

Medicaments produced using the NSAID and opioid analgesic (simply,hereinafter, medicaments of the invention) may take a wide variety offorms but are preferably suitable for oral administration and, in thiscase, are especially preferred to be in unit dosage form although bulkforms such as syrups, suspensions or linctuses may also be employed.Where the medicament is in unit dosage form it may, for example, be inthe form of a tablet or filled capsule (filled with a liquid fill or aparticulate or solid fill). The unit dosage form may be formulated togive immediate release of the active ingredients upon administration ormay be, adapted to give delayed or sustained release or, in indeed, acombination of both immediate and delayed or sustained release.

Suitable materials for inclusion in a controlled release matrix include,for example

(a) Hydrophilic or hydrophobic polymers, such as gums, cellulose esters,cellulose ethers, protein derived materials, nylon acrylic resins,polylactic acid, polyvinylchloride, starches, polyvinylpyrrolidones, andcellulose acetate phthalate. Of these polymers, cellulose ethersespecially substituted cellulose ethers such as alkylcelluloses (such asethylcellulose), C₁ -C₆ hydroxyalkylcelluloses (such ashydroxypropylcellulose and especially hydroxyethyl cellulose) andacrylic resins (for example methacrylates such as methacrylic acidcopolymers) are preferred. The controlled release matrix mayconveniently contain between 1% and 80% (by weight) of the hydrophilicor hydrophobic polymer.

(b) Digestible, long chain (C₈ -C₅₀, especially C₈ -C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, hydrogenated vegetableoils such as Cutina (Trade Mark), fatty alcohols (such as lauryl,myristyl, stearyl, cetyl or preferably cetostearyl alcohol), glycerylesters of fatty acids for example glyceryl monostearate mineral oils andwaxes (such as beeswax, glycowax, castor wax or carnauba wax).Hydrocarbons having a melting point of between 25° C. and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The matrix may contain up to 60% (by weight) ofat least one digestible, long chain hydrocarbon.

(c) Polyalkylene glycols. The matrix may contain up to 60% (by weight)of at least one polyalkylene glycol.

A suitable matrix comprises one or more cellulose ethers or acrylicresins, one or more C₁₂ -C₃₆, preferably C₁₄ -C₂₂, aliphatic alcoholsand/or one or more hydrogenated vegetable oils.

A particularly suitable matrix comprises one or more alkylcelluloses,one or more C₁₂ -C₃₆, (preferably C₁₄ -C₂₂) aliphatic alcohols andoptionally one or more polyalkylene glycols.

Preferably the matrix contains between 0.5% and 60%, especially between1% and 50% (by weight) of the cellulose ether.

The acrylic resin is preferably a methacrylate such as methacrylic acidcopolymer USNF Type A (Eudragit L, Trade Mark), Type B (Eudragit S,Trade Mark), Type C (Eudragit L 100-55, Trade Mark), Eudragit NE 30D,Eudragit E, Eduragit RL and Eudragit RS. Preferably the matrix containsbetween 0.5% and 60% by weight, particularly between 1% and 50% byweight of the acrylic resin.

In the absence of polyalkylene glycol, the matrix preferably containsbetween 1% and 40%, especially between 2% and 36% (by weight) of thealiphatic alcohol. When polyalkylene glycol is present in the oraldosage form, then the combined weight of the aliphatic alcohol and thepolyalkylene glycol preferably constitutes between 2% and 40%,especially between 2 and 36% (by weight) of the matrix.

The polyalkylene glycol may be, for example, polypropylene glycol or,which is preferred, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferably between 200and 15000 especially between 400 and 12000.

The medicament-containing controlled release matrix can readily beprepared by dispersing the active ingredient in the controlled releasesystem using conventional pharmaceutical techniques such as wetgranulation, dry blending, dry granulation or coprecipitation.

Sustained release formulation may also be produced by spheronizing theactive ingredient(s) with a spheronizing agent such as microcrystallinecellulose. Further, the active ingredients my be melt pelletized inconjunction with a hydrophobic fusible carrier, for example hydrogenatedcastor oil, hydrogenated vegetable oil, beeswax or carnauba wax. Ifdesired, a dissolution release control agent may be employed togetherwith the fusible carriers and examples of such include water-solubleorganic materials such as polyalkylene glycols or powdered solids suchas dicalcium phosphate.

The content of NSAID and opioid analgesic in any particular dosage formwill depend upon a number of variables including the number of dosesintended to be administered per day and the intended daily dosage.

The effectiveness of an NSAID/opioid analgesic combination hag beenevidenced by animal tests.

Polyarthritis was induced in 14 groups of rats (n=6 per group) via aninjection of adjuvant material into the base of the tail. Two naivegroups were used as controls (n=6 per group). Each group received adifferent regimen of treatment, i.e., indomethacin, morphine orcombination (i.e. morphine+indomethacin) in either high or low doses,from day 0 or when a clinical sign of adjuvant disease first becameapparent. The arthritic control group received no treatment over thecourse of the experiment. Daily during the experiment, footpad diametersand clinical scores were measured. On day 21 the rats were sacrificedand their hindlimbs radiographed.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS EXAMPLE 1

Male Wistar rats weighing 200-300 g, were kept in groups of 6, in cagesmaintained at a temperature of 20° C. with 12 hours light, cleanedweekly and fed lab chow and water ad libitum.

Acute polyarthritis was induced by a single intradermal injection of 0.1mull of 10 mg/mull suspension of adjuvant (heat killed mycobacteriumtuberculosis in sterile paraffin oil), into the base of the tail. Naiveanimals were used as controls.

The exclusion criteria for the study were lethargy, poor fur condition,nasal discharge and diarrhoea.

Chronic administration of the two experimental drugs, morphine andindomethacin, was performed by daily dosing.

(1) Morphine in 0.1% sodium metabisulphate (Martindale Pharmaceuticals),was diluted to 5 ml/ml and 0.5 mg/ml in 0.9% sterile saline. Themorphine was administered as a bolus by intraperitoneal injection.

(2) Indomethacin (Sigma), 2.5 mg/ml and 0.5 mg/ml solutions wereprepared in 2% sodium bicarbonate. The pH was then adjusted to 7. Theindomethacin was administered as a bolus orally.

The rats were divided into the following experimental groups:

    ______________________________________    A - HIGH DOSE GROUPS    Group 1           Morphine 5 mg/kg/day given from the onset of           clinically apparent disease.    Group 2           Indomethacin 2.5 mg/kg/day given from the onset of           clinically apparent disease.    Group 3           Morphine 5 mg/kg/day and indomethacin 2.5 mg/kg/day           given from the onset of clinically apparent disease.    Group 4           Arthritic control group.    Group 5           Naive control group.    B - LOW DOSE GROUPS    Group 6           Morphine 0.5 mg/kg/day given from the day onset of           clinically apparent disease.    Group 7           Indomethacin 0.5 mg/kg/day given from the onset of           clinically apparent disease.    Group 8           Morphine 0.5 mg/kg/day and indomethacin 0.5 mg/kg/day           given from onset of clinically apparent disease.    Group 9           Arthritic control group.    Group 10           Naive control group.    ______________________________________

DISEASE ASSESSMENT

The rats were examined daily, over the 21 day period for the followingparameters:

(a) CLINICAL SCORE

The rats were clinically scored, as described below.

Clinical score 0=No inflammation.

Clinical score of 1=Slight redness and swelling of the foot.

Clinical score of 2=Foot swelling such that tendons were no longervisible.

Clinical score of 3=Gross inflammation and deformity of the ankle joint.

(b) HINDLIMB FOOTPAD DIAMETER

The footpad diameter of both hindlimbs were measured using verniercallipers at a designated level/point on the rats hindlimb (inmillimeters).

(c) RADIOLOGICAL ASSESSMENT

Using a faxitron machine, hind limbs were exposed to the x-ray sourcefor 25 minutes (5×5 minute exposures) at 40 KVP. X-ray films weredeveloped, fixed and then placed in slides for view on an overheadprojector for assessment.

Each radiograph of the rat hindfoot, was evaluated blindly for thepresence and severity of the following parameters.

(1) Bone mineralization

Grade 0=Normal.

Grade 1=Mild juxtaarticular osteoporosis only.

Grade 4=Severe osteoporosis with pathologic fractures.

(2) Erosions

Grade 0=None.

Grade 1=Small bony irregularities at corners of articular surfaces.

Grade 4=Complete destruction of articular surfaces.

(3) Periostitis

Grade 0=None.

Grade 1=Thin delicate layer of subperiosteal new bone involving thedistal tibia or plantar surface of the tarsus.

Grade 4=severe irregular bony proliferation cloaking the entire ankleregion.

(4) Cartilage space

Grade 0=Normal.

Grade 1=Slight joint space narrowing.

Grade 4=Bony ankylosis and destruction of cartilage.

(5) Soft tissue swelling

Grade 0=Normal.

Grade 1=Slight particular soft tissue swelling.

Each radiograph was scored blindly of the presence and severity of thefive parameters shown above.

A grade of 0 to 4 (with 0 equalling normal and 4 equalling severechanges as stipulated above) was assigned for each of the above fivepossible findings. A total score of the sum of each individual grade forany given rat was then obtained. Thus the maximum total score any ratcould receive was 20.

The results obtained are shown graphically in FIGS. 1-6 of theaccompanying drawings.

EXAMPLE 2

A further adjuvant arthritis study was carried out using a protocolsimilar to that of Experimental 1 (see also "Models for Arthritis, thesearch for anti-arthritic drugs" Chapter 1, Billingham M.E.T., 1990pages 1-47, Pergammon Press). The effects of morphine and indomethacingiven alone or in combination on clinical score and joint diameter; andradiological and histological scores were assessed. The results of thisstudy are shown in FIGS. 7 and 8.

Combination therapy (indomethacin 0.5 mg/kg/day plus morphine 0.25;0.50; 1.00 and 2.00 mg/kg/day) produced significant suppression ofclinical score FIG. 7a, joint diameter FIG. 7b, radiological score FIG.8a and histological score 8b when compared to untreated arthritic groupsor groups treated individually with either compound. It is believed thata synergistic as opposed to an additive effect is operating.

It is observed that the suppressive effect of the combination treatmenton the arthritic disease process parameters occurs over the whole rangeof morphine administered.

EXAMPLE 3

An MBSA study (Breckertz D. et al, Arthritis and Rheumatism, Vol 20,page 841-850, 1977) was carried out to determine the effects of opioidand non-steroidal anti-inflammatory drugs on synovial vascular responsesand whether combination therapy of these compounds would have asuppressive effect on this parameter. The influence of morphine,codeine, indomethacin and ibuprofen given alone or in combination onbasal extravasation was assessed.

As shown in FIG. 9a morphine and indomethacin produced suppression ofbasal plasma extravasation which was not statistically significantwhilst, in contrast, combination therapy gave significant suppression ofbasal plasma extravasation compared to untreated animals. The dosagesmade were 0.5 mg/kg/day indomethacin and 1.0 mg/kg/day morphine. As canbe seen the combination therapy was more effective at reducing basalplasma extravasation compared to either drug individually.

As shown in FIG. 9b combination therapy with oral codeine and ibuprofenalso produced significant suppression of basal plasma extravasation, theresults mirroring those obtained with morphine and indomethacin. Thedosages used were 2.5 mg/kg/day codeine phosphate and 5 mg/kg/dayibuprofen.

The above experimental studies demonstrate that combination therapy witha non-steroidal anti-inflammatory and an opioid drug, for example,morphine and indomethacin and codeine and ibuprofen can substantiallyinhibit the arthritic disease process.

In particular the response between opioid and non-steroidalanti-inflammatory drugs has been found to occur in peripheral tissue andunexpectedly low doses of orally administered opioid and non-steroidalanti-inflammatory drugs can produce a surprisingly beneficial clinicaleffect.

In order that the invention may be well understood the followingExamples of composition prepared in accordance with the invention aregiven by way of illustration only.

    ______________________________________    EXAMPLE 1                     mg/Capsule    ______________________________________    Indomethacin       10.0    Morphine sulphate  20.0    Lactose            118.5    Talc               0.75    Colloidal anhydrous silica                       0.75    Total              150.0    ______________________________________

    ______________________________________    EXAMPLE 2                     mg/Capsule    ______________________________________    Diclofenac sodium  75.0    Codeine phosphate  37.5    Lactose            85.5    Talc               1.0    Colloidal anhydrous silica                       1.0    Total              200.0    ______________________________________

    ______________________________________    EXAMPLE 3                     mg/Capsule    ______________________________________    Ibuprofen          300.0    Codeine phosphate  15.0    Lactose            81.0    Talc               2.0    Colloidal anhydrous silica                       2.0    Total              400.0    ______________________________________

While the invention has been illustrated with respect to the productionand use of a particular compound, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention.

What is claimed is:
 1. A method for the inhibition of an arthritisdisease process in a patient in need thereof, the methodcomprising:administering ibuprofen or pharmaceutically acceptable saltsthereof and codeine or pharmaceutically acceptable salts thereof, insynergistic amounts and in a ratio of ibuprofen:codeine from about 240:1to about 0.97:1 and for a duration effective to inhibit an arthritisdisease process in a patient in need thereof.
 2. The method according toclaim 1, wherein least one of said drugs is in a solid oral dosage form.3. The method according to claim 1, wherein at least one of said drugsis suitable for dosing once or twice a day.
 4. The method according toclaim 1 wherein said ibuprofen is administered in a daily dose rangingfrom about 300 to about 2400 mg and said codeine is administered in adaily dose ranging from about 12.5 to about 310 mg.
 5. The method ofclaim 1, wherein said arthritis disease is osteoarthritis.
 6. The methodof claim 1, wherein said arthritis disease is rheumatoid arthritis. 7.The method of claim 3, said oral dosage form comprising 5 to 150 mgcodeine sulfate and 150 to 1200 mg ibuprofen.
 8. The method of claim 2,said oral dosage form selected from the group consisting of a syrupsuspension, linctus tablet or filled capsule.
 9. The method of claim 3,said oral dosage form being formulated to provide a sustained release ofat least a position of said ibuprofen or said codeine.
 10. The method ofclaim 9, said oral dosage, form further comprising a hydrophilic orhydrophobic polymer, a long chain hydrocarbon, and a polyalkyleneglycol.
 11. The method of claim 1, wherein the ratio ofibuprofen:codeine is from about 192:1 to about 1:1.
 12. The method ofclaim 1, wherein the ratio of ibuprofen:codeine is about 2:1, with theamount of codeine being calculated as the phosphate salt thereof.
 13. Amethod for the inhibition of an arthritis disease process in a patientin need thereof, the method comprising:administering ibuprofen orpharmaceutically acceptable salts thereof and codeine orpharmaceutically acceptable sats thereof, in synergistic amounts and ina ratio of ibuprofen:codeine from about 240:1 to about 0.97:1 and for aduration effective to inhibit an arthritis disease process in a patientin need thereof, wherein said ibuprofen is administered in a daily doseranging from about 300 to about 2400 mg and said codeine is administeredin a daily dose ranging from about 12.5 to about 310 mg.
 14. A methodfor the inhibition of an arthritis disease process in a patient in needthereof, the method comprising:administering ibuprofen orpharmaceutically acceptable salts thereof and codeine orpharmaceutically acceptable salts thereof, in synergistic amounts andfor a duration effective to inhibit an arthritis disease process in apatient in need thereof, wherein said ibuprofen is administered in adaily dose ranging from about 300 to about 2400 mg and said codeine isadministered in a daily dose ranging from about 12.5 to about 310 mg.